bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–04–13
eighteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
  2. Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.
  3. Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.
  4. Pre-existing intratumoral stem-like CD8+ T cells drive radiotherapy-induced tumor immunity.
  5. Brief blockade of type I IFN increases CD8+ T cell memory.
  6. Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.
  7. The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia.
  8. Erratum for the Research Article: "SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8+ T cell cytotoxic function" by X. Liu et al.
  9. Fatty acid binding proteins-mediated mitochondrial dysfunction in the development of age-related diseases: A review.
  10. The diversity of CD8+ T cell dysfunction in cancer and viral infection.
  11. Recent Advances in Aging and Immunosenescence: Mechanisms and Therapeutic Strategies.
  12. T cells with a taste for tissue remodeling.
  13. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives.
  14. Mild Uncoupling of Mitochondria Synergistically Enhances Senolytic Specificity and Sensitivity of BH3 Mimetics.
  15. Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection.
  16. Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance.
  17. Multiple roles of branched-chain amino acid metabolism in tumour progression.
  18. Extracellular Vesicles in Aging and Age-Related Diseases. How Important Are They?
  1. Cell Death Discov. 2025 Apr 09. 11(1): 161
    Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
    Li Liu, Zhanying Hao, Xi Yang, Yan Li, Siyang Wang, Linze Li.
      The complex interplay between cancer progression and immune senescence is critically influenced by metabolic reprogramming in T cells. As T cells age, especially within the tumor microenvironment, they undergo significant metabolic shifts that may hinder their proliferation and functionality. This manuscript reviews how metabolic alterations contribute to T cell senescence in cancer and discusses potential therapeutic strategies aimed at reversing these metabolic changes. We explore interventions such as mitochondrial enhancement, glycolytic inhibition, and lipid metabolism adjustments that could rejuvenate senescent T cells, potentially restoring their efficacy in tumor suppression. This review also focuses on the significance of metabolic interventions in T cells with aging and further explores the future direction of the metabolism-based cancer immunotherapy in senescent T cells.
    DOI:  https://doi.org/10.1038/s41420-025-02468-y
  2. J Immunol. 2025 Apr 09. pii: vkaf034. [Epub ahead of print]
    Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.
    KayLee K Steiner, Arissa C Young, Andrew R Patterson, Ayaka Sugiura, McLane J Watson, Samuel E J Preston, Anton Zhelonkin, Erin Q Jennings, Channing Chi, Darren R Heintzman, Andrew P Pahnke, Yasmine T Toudji, Zaid Hatem, Matthew Z Madden, Emily N Arner, Allison E Sewell, Allison K Blount, Richmond Okparaugo, Emilia Fallman, Evan S Krystofiak, Ryan D Sheldon, Katherine N Gibson-Corley, Kelsey Voss, Sara M Nowinski, Russell G Jones, Denis A Mogilenko, Jeffrey C Rathmell.
      Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These T cell subsets rely on distinct metabolic programs, modulation of which differentially affects T cell fate and function. Lipid metabolism is fundamental yet remains poorly understood across CD4+ T cell subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid metabolism genes and pathways essential for T cell functions. These screens established mitochondrial fatty acid synthesis genes Mecr, Mcat, and Oxsm as key metabolic regulators. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD4+ and CD8+ T cell numbers, demonstrating that MECR is not essential in homeostatic conditions. However, effector and memory T cells were reduced in Mecr knockout and MECR-deficient CD4+ T cells and proliferated, differentiated, and survived less well than control T cells. Interestingly, T cells ultimately showed signs of mitochondrial stress and dysfunction in the absence of MECR. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced tricarboxylic acid intermediates, and accumulated intracellular iron, which appeared to contribute to increased cell death and sensitivity to ferroptosis. Importantly, MECR-deficient T cells exhibited fitness disadvantages and were less effective at driving disease in an in vivo model of inflammatory bowel disease. Thus, MECR-mediated metabolism broadly supports CD4+ T cell proliferation and survival in vivo. These findings may also provide insight to the immunological state of MECR- and other mitochondrial fatty acid synthesis-deficient patients.
    Keywords:  CD4+ T cells; MECR; lipid metabolism; mtFAS
    DOI:  https://doi.org/10.1093/jimmun/vkaf034
  3. J Exp Med. 2025 Jun 02. pii: e20241102. [Epub ahead of print]222(6):
    Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.
    Ana Belén Plata-Gómez, Ping-Chih Ho.
      The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.
    DOI:  https://doi.org/10.1084/jem.20241102
  4. Cell Rep. 2025 Apr 10. pii: S2211-1247(25)00337-7. [Epub ahead of print]44(4): 115566
    Pre-existing intratumoral stem-like CD8+ T cells drive radiotherapy-induced tumor immunity.
    Hakan Köksal, Michael Herbst, Paulo Perreira, Marc Nater, Nicola Regli, Cheïma Boudjeniba, Nese Erdem Borgoni, Virginia Cecconi, Maries van den Broek.
      CD8+ T cells are crucial for both spontaneous and therapy-induced restriction of tumor progression. Although many patients with cancer undergo radiotherapy, the precise effect of this genotoxic treatment on tumor-associated CD8+ T cells is insufficiently understood. Here, we investigated the influence of radiotherapy on intratumoral CD8+ T cells. We found that, although these CD8+ T cells initially decline following radiotherapy, they subsequently expand and are both essential and sufficient for early tumor control. In response to radiotherapy, stem-like CD8+ T cells proliferate and differentiate into effector CD8+ T cells, making them key drivers of tumor immunity. Our findings underscore the pivotal role of intratumoral stem-like CD8+ T cells in mediating radiotherapy-induced anti-tumor immunity and provide deeper insights into the dynamic behavior of CD8+ T cells during tumor control after radiotherapy.
    Keywords:  CP: Cancer; CP: Immunology; TCF-1; cancer; radiotherapy; stem-like CD8(+) T cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.115566
  5. Nat Rev Immunol. 2025 Apr 08.
    Brief blockade of type I IFN increases CD8+ T cell memory.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-025-01171-4
  6. Cell Metab. 2025 Apr 02. pii: S1550-4131(25)00106-8. [Epub ahead of print]
    Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.
    Seyedeh Sahar Mortazavi Farsani, Jignesh Soni, Lu Jin, Anil Kumar Yadav, Shivani Bansal, Tian Mi, Leena Hilakivi-Clarke, Robert Clarke, Benjamin Youngblood, Amrita Cheema, Vivek Verma.
      Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and 13C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions. PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells, enhancing adoptive cell therapy. In preclinical models, the PKM2 agonist induced CD8 T cell-dependent anti-tumor responses that synergized with anti-programmed death 1 (PD1) therapy. Immunologically, PKM2 agonists boosted the activation of effector T cells while reducing FoxP3+ T regulatory (Treg) cells in the tumors. The anti-PD1 combination enhanced the frequency of tumor-specific activated CD8 T cells. Together, PKM2 agonism increased mitochondrial functions supporting cell cytotoxicity. Hence, pharmacological targeting of PKM2 can be a clinically viable strategy for enhancement of adoptive cell therapy, in situ anti-tumor immune responses, and immune checkpoint blockade therapy. VIDEO ABSTRACT.
    Keywords:  CD8 T cells; PD1 blockade; PKM2; adoptive cell therapy; immunotherapy; melanoma; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.003
  7. Br J Haematol. 2025 Apr 09.
    The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia.
    Zhuanzhen Zheng, Wenjing Wang, Mengjing Feng, Xiuhua Chen, Fanggang Ren, Yanfei Hou.
      Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) link to unfavourable prognoses. We explored the mechanism of enhancer of zeste homologue 2/histone H3 of lysine 27 (EZH2/H3K27me3) downregulating C-X-C motif chemokine 10 (CXCL10) to affect CD8+ T-cell exhaustion, participating in MDS-to-AML transformation. NHD13 mice were treated with GSK126 (EZH2 inhibitor) and CXCL10 neutralizing antibody, with transformation time, blood cell counts and CD8+ T cell determined. SKM-1 cells treated with short hairpin-EZH2, overexpressing-EZH2, GSK126 and CXCL10 were co-cultured with CD8+ T cells. EZH2, CXCL10, H3K27me3 and EZH2 levels and EZH2 enzyme activity were assessed. CD8+ T-cell cytotoxicity, exhaustion, apoptosis and SKM-1 cell malignant behaviours were evaluated. In vivo, EZH2 inhibition upregulated CXCL10, decelerating MDS to AML transformation and delaying CD8+ T-cell exhaustion. EZH2 inhibition elevated peripheral blood cells, alleviated splenomegaly, reduced CD8+ T cells, elevated CD8+ T cytotoxicity and abated CD8+ T-cell exhaustion in NHD13 mice. CXCL10 neutralizing antibody accelerated AML transformation by inhibiting CD8+ T-cell exhaustion via EZH2. In vitro, EZH2 overexpression facilitated CD8+ T-cell exhaustion and SKM-1 cell malignant behaviours. EZH2-mediated H3K27me3 curbed CXCL10 transcription and secretion. Collectively, EZH2/H3K27me3 downregulates CXCL10 to facilitate CD8+ T-cell exhaustion, accelerating transformation from MDS to AML.
    Keywords:  CD8+ T cells; C‐X‐C motif chemokine 10; acute myeloid leukaemia; enhancer of zeste homologue 2; histone H3 of lysine 27; histone methylation; immune escape; myelodysplastic syndrome
    DOI:  https://doi.org/10.1111/bjh.20066
  8. Sci Adv. 2025 Apr 11. 11(15): eadx5774
    Erratum for the Research Article: "SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8+ T cell cytotoxic function" by X. Liu et al.
      
    DOI:  https://doi.org/10.1126/sciadv.adx5774
  9. Int J Biol Macromol. 2025 Apr 07. pii: S0141-8130(25)03465-8. [Epub ahead of print] 142913
    Fatty acid binding proteins-mediated mitochondrial dysfunction in the development of age-related diseases: A review.
    Xingxing Ren, Chaoyuan Jin, Qilin Li, Congyi Fu, Yu Fang, Zihang Xu, Zi Liang, Tianshi Wang.
      Fatty acid-binding proteins (FABPs) act as lipid chaperones and play a role in the pathological processes of various lipid signaling pathways. Mitochondria are crucial for the regulation of lipid metabolism. As an aging marker, lipid-mediated mitochondrial dysfunction has been observed in the etiology of numerous diseases, including neurodegenerative diseases, metabolic syndromes, cardiovascular diseases, and tumorigenesis. Members of the FABP family have been identified to regulate mitochondrial function. Targeting FABPs specifically may provide a promising approach to improve mitochondrial function and treat age-related diseases. This review summarizes the connection between FABPs and mitochondrial function and highlights certain FABPs involved in age-related diseases that hold significant therapeutic promise.
    Keywords:  Aging; Cardiovascular diseases; FABPs; Metabolic syndromes; Mitochondria; Neurodegenerative diseases; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142913
  10. Nat Rev Immunol. 2025 Apr 11.
    The diversity of CD8+ T cell dysfunction in cancer and viral infection.
    Lorenzo Galluzzi, Kellie N Smith, Adrian Liston, Abhishek D Garg.
      CD8+ T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as exhaustion. There have been considerable efforts to develop therapeutic strategies that prevent exhaustion in these pathological scenarios, but there has been limited success. This may be because exhaustion is not the only source of T cell hypofunction in cancer and chronic viral infection. Here, we discuss the molecular and spatiotemporal mechanisms beyond exhaustion that underlie the inability of CD8+ T cells to eradicate malignant or chronically infected cells. We also propose a framework to enhance our understanding of these mechanisms - which include tolerization, anergy, senescence, cell death, exclusion and ignorance - with the ultimate aim of informing novel approaches to improve the clinical management of cancer and chronic viral infection.
    DOI:  https://doi.org/10.1038/s41577-025-01161-6
  11. Cells. 2025 Mar 27. pii: 499. [Epub ahead of print]14(7):
    Recent Advances in Aging and Immunosenescence: Mechanisms and Therapeutic Strategies.
    Shuaiqi Wang, Tong Huo, Mingyang Lu, Yueqi Zhao, Jianmin Zhang, Wei He, Hui Chen.
      Cellular senescence is an irreversible state of cell cycle arrest. Senescent cells (SCs) accumulate in the body with age and secrete harmful substances known as the senescence-associated secretory phenotype (SASP), causing chronic inflammation; at the same time, chronic inflammation leads to a decrease in immune system function, known as immunosenescence, which further accelerates the aging process. Cellular senescence and immunosenescence are closely related to a variety of chronic diseases, including cardiovascular diseases, metabolic disorders, autoimmune diseases, and neurodegenerative diseases. Studying the mechanisms of cellular senescence and immunosenescence and developing targeted interventions are crucial for improving the immune function and quality of life of elderly people. Here, we review a series of recent studies focusing on the molecular mechanisms of cellular senescence and immunosenescence, the regulation of aging by the immune system, and the latest advances in basic and clinical research on senolytics. We summarize the cellular and animal models related to aging research, as well as the mechanisms, strategies, and future directions of aging interventions from an immunological perspective, with the hope of laying the foundation for developing novel and practical anti-aging therapies.
    Keywords:  SASP; aging; cellular senescence; immunosenescence; senolytic
    DOI:  https://doi.org/10.3390/cells14070499
  12. Immunity. 2025 Apr 08. pii: S1074-7613(25)00131-1. [Epub ahead of print]58(4): 781-783
    T cells with a taste for tissue remodeling.
    Greet Verstichel, Hilde Cheroutre.
      Specialized T cells can support tissue remodeling, but how T cells contribute to mammary gland remodeling during pregnancy is not fully understood. In a recent Cell issue, Corral et al. demonstrate that self-sensing T cells migrate to the mammary gland where they optimize milk production.
    DOI:  https://doi.org/10.1016/j.immuni.2025.03.012
  13. Front Immunol. 2025 ;16 1563303
    Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives.
    Xuan-Yu Gu, Jia-Li Yang, Rui Lai, Zheng-Jun Zhou, Dan Tang, Long Hu, Li-Jin Zhao.
      Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both tumor progression and immune dynamics. As a byproduct of aerobic glycolysis, lactate satisfies the metabolic needs of proliferating tumor cells while reshaping the TME to facilitate immune evasion. Elevated lactate levels inhibit effector immune cells such as CD8+ T and natural killer cells, while supporting immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, thus fostering an immunosuppressive environment. Lactate promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, and activates nuclear factor kappa B, leading to further immunological dysfunction. In this review, we examined the role of lactate in metabolic reprogramming, immune suppression, and treatment resistance. We also discuss promising therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase inhibitors, monocarboxylate transporter inhibitors, and TME neutralization methods, all of which can restore immune function and enhance immunotherapy outcomes. By highlighting recent advances, this review provides a theoretical foundation for integrating lactate-targeted therapies into clinical practice. We also highlight the potential synergy between these therapies and current immunotherapeutic strategies, providing new avenues for addressing TME-related challenges and improving outcomes for patients with cancer.
    Keywords:  immunosuppression; immunotherapy; lactate metabolism; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1563303
  14. Aging Biol. 2024 Feb 20. 1(1): 20240022
    Mild Uncoupling of Mitochondria Synergistically Enhances Senolytic Specificity and Sensitivity of BH3 Mimetics.
    Edward P Fielder, Abbas Ishaq, Evon Low, Joseph A Laws, Aisha Calista, Jemma Castle, Thomas von Zglinicki, Satomi Miwa.
      Despite immense potential as anti-aging interventions, applications of current senolytics are limited due to low sensitivity and specificity. We demonstrate the specific loss of complex I-linked coupled respiration and the inability to maintain mitochondrial membrane potential upon respiratory stimulation as a specific vulnerability of senescent cells. Further decreasing the mitochondrial membrane potential of senescent cells with a mitochondrial uncoupler synergistically enhances the in vitro senolytic efficacy of BH3 mimetic drugs, including Navitoclax, by up to two orders of magnitude, whereas non-senescent cells remain unaffected. Moreover, a short-term intervention combining the mitochondrial uncoupler BAM15 with Navitoclax at a dose two orders of magnitude lower than typically used rescues radiation-induced premature aging in an in vivo mouse model, as demonstrated by reduced frailty and improved cognitive function for at least eight months. Our study shows compromised mitochondrial functional capacity is a senescence-specific vulnerability that can be targeted by mild uncoupling in vitro and in vivo.
    DOI:  https://doi.org/10.59368/agingbio.20240022
  15. JCI Insight. 2025 Apr 08. pii: e186259. [Epub ahead of print]10(7):
    Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection.
    Anna B Morris, Max W Adelman, Kelsey B Bennion, Catherine D Martinez, Kem-Maria McCook, Michael H Woodworth, Charles R Langelier, Nadine Rouphael, Christopher D Scharer, Cheryl L Maier, Colleen S Kraft, Mandy L Ford.
      While the inhibitory receptor FcγRIIB has been shown to be upregulated on activated CD8+ T cells in both mice and humans, its effect on T cell fate during infection has not been fully elucidated. We identified an increase in FcγRIIB-expressing CD8+ T cells in patients with COVID-19 relative to healthy controls as well as in mouse models of viral infection. Despite its well-known role as an Fc receptor, FcγRIIB also ligates the immunosuppressive cytokine Fgl2, resulting in CD8+ T cell apoptosis. Both chronic LCMV infection in mice and COVID-19 in humans resulted in a significant increase in plasma Fgl2. Transfer of CD8+ T cells into a Fgl2-replete, but not Fgl2-devoid, environment resulted in elimination of FcγRIIB+, but not FcγRIIB-, CD8+ T cells. Similarly, plasma Fgl2 was directly proportional to CD8+ T cell lymphopenia in patients with COVID-19. RNA-Seq analysis demonstrated that Fgl2 was produced by murine virus-specific CD8+ T cells, with an increase in Fgl2 in CD8+ T cells elicited during chronic versus acute viral infection. Fgl2 was also upregulated in CD8+ T cells from patients with COVID-19 versus healthy controls. In summary, CD8+ T cell production of Fgl2 during viral infection underpinned an FcγRIIB-mediated loss of CD8+ T cell immunity in both mice and humans.
    Keywords:  Adaptive immunity; Immunology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.186259
  16. Front Immunol. 2025 ;16 1573686
    Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance.
    Lanyue Zhang, Jiangnan Zhao, Chunyu Su, Jianxi Wu, Lai Jiang, Hao Chi, Qin Wang.
      Metabolic reprogramming is a hallmark of ovarian cancer, enabling tumor progression, immune evasion and drug resistance. The tumor microenvironment (TME) further shapes metabolic adaptations, enabling cancer cells to withstand hypoxia and nutrient deprivation. While organoid models provide a physiologically relevant platform for studying these processes, they still lack immune and vascular components, limiting their ability to fully recapitulate tumor metabolism and drug responses. In this study, we investigated the key metabolic mechanisms involved in ovarian cancer progression, focusing on glycolysis, lipid metabolism and amino acid metabolism. We integrated metabolomic analyses and drug sensitivity assays to explore metabolic-TME interactions using patient-derived, adult stem cell-derived and iPSC-derived organ tissues. Among these, we found that glycolysis, lipid metabolism and amino acid metabolism play a central role in tumor progression and chemotherapy resistance. We identified methylglyoxal (MGO)-mediated BRCA2 dysfunction as a driver of immune escape, a role for sphingolipid signaling in tumor proliferation and a role for kynurenine metabolism in CD8+ T cell suppression. In addition, PI3K/AKT/mTOR and Wnt/β-catenin pathways promote chemoresistance through metabolic adaptation. By elucidating the link between metabolic reprogramming and immune evasion, this study identifies key metabolic vulnerabilities and potential drug targets in ovarian cancer. Our findings support the development of metabolically targeted therapies and increase the utility of organoid-based precision medicine models.
    Keywords:  drug resistance; immune escape; metabolic reprogramming; molecular mechanisms; organoid; ovarian cancer; personalized therapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1573686
  17. J Biomed Sci. 2025 Apr 09. 32(1): 41
    Multiple roles of branched-chain amino acid metabolism in tumour progression.
    Lin Wang, Feng Shi, Ya Cao, Longlong Xie.
      Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt to the ever-changing microenvironment. Branched-chain amino acids (BCAAs) and their metabolites are involved in intracellular protein synthesis and catabolism, signal transduction, epigenetic modifications, and the maintenance of oxidative homeostasis. Alterations in BCAA metabolism can influence the progression of various tumours. However, how BCAA metabolism is dysregulated differs among depending on tumour type; for example, it can manifest as decreased BCAA metabolism leading to BCAA accumulation, or as enhanced BCAA uptake and increased catabolism. In this review, we describe the role of BCAA metabolism in the progression of different tumours. As well as discuss how BCAA metabolic reprogramming drives tumour therapy resistance and evasion of the antitumour immune response, and how these pro-cancer effects are achieved in part by activating the mTORC signalling pathway. In-depth investigations into the potential mechanisms by which BCAA metabolic reprogramming affects tumorigenesis and tumour progression can enhance our understanding of the relationship between metabolism and cancer and provide new strategies for cancer therapy.
    Keywords:  BCAA metabolism; Metabolic reprogramming; Tumour immunity; Tumour progression; Tumour resistance; mTORC signalling pathway
    DOI:  https://doi.org/10.1186/s12929-025-01132-y
  18. Adv Biol (Weinh). 2025 Apr 09. e2400656
    Extracellular Vesicles in Aging and Age-Related Diseases. How Important Are They?
    David J Lundy, Chia-Te Liao.
      Extracellular vesicles (EVs), lipid bilayer-bound particles secreted by cells, have attracted significant research attention for their roles in aging-related disorders, including cardiovascular disease, metabolic dysfunction, cancer, and neurodegeneration. Research shows that EV cargo and function are influenced by factors including age, disease state, exercise, nutrition and sleep, and they may modulate various aging-associated processes such as stem cell renewal, nutrient sensing, cell senescence, mitochondrial function, and insulin resistance. This perspective highlights, for a general audience, a selection of studies of EVs in aging and age-related diseases, and their diverse roles in organ crosstalk. While current evidence indicates that EVs play multiple roles in aging, there are numerous challenges including methodological challenges and limitations, heterogeneous reports of EV cargo, limited reproducibility, and apparent context-dependent effects of EVs and their cargo. Together, this limits the interpretation of these studies. This is proposed that EVs may act as fine-tuners of cellular communication within the broader aging-associated secretome and the importance of standardizing methods are emphasized. Last, future directions for EV research are suggested.
    Keywords:  ageing; exosome; miRNA; plasma
    DOI:  https://doi.org/10.1002/adbi.202400656
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